JPH07504890A - Synergistic effect of NMDA antagonists - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Name of the Invention: Synergistic effect of N M D A antagonist The present invention relates to an excitatory amino acid antagonist Another aspect of the invention that relates to the method of obtaining a synergistic effect of a group of therapeutic effects is the prevention of hyperexcitability. Novel pharmaceutical compositions useful for treating conditions associated with amino acid activity.

According to the present invention, proheneside synergistically potentiates the activity of the following excitatory amino acid antagonists: It was discovered that

[During the ceremony, a) in the compounds of formula 1a, X represents linear C2-c4 alkylene or S; m is an integer from 1 to 4, and 2 is H1C1-C4 alkyl, phenyl, substituted phenyl or alkylphenyl in which the phenyl ring may be optionally substituted Represents a substituent, R is hydrogen, halogen, ct~C4 alkyl, C, ~C4 alkyl Kishi, CF,,OCF.

Represents OH, No, or CN, and R1 and R2 are respectively German or -〇-(CH2) II-NR6R7, where n is an integer from 1 to 4, and R3 is C1 to c4. alkyl, phenyl, substituted phenyl, or phenyl ring is optionally additionally substituted represents an alkylphenyl substituent which may be represents hydrogen or Ct-C4 alkyl, and R6 and R7 each independently represent hydrogen or Ct-C4 alkyl; 8-c4 alkyl or R6 and R7 together with adjacent nitrogen atoms form a lysino, morpholino or pyrrolidino group, provided that X is C, ~C4 alkyl If it is len, then m must be 0.

b) In compounds of formula +b, R, Z and R2 are as above, B is hydrogen, C 1-c4 alkyl, optionally optionally substituted alkylphenyl, or -CH2-C0R2, Y is S02 or CO, A is phenyl, a II phenyl or C(0)D, where D is defined as R2 above.

C) in compounds of formula 1c, E represents hydrogen, C1-C4 alkyl or -CF3; , A represents a methylene or trimethylene bridging group, El is hydrogen, C1 to C4 atom alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, or substituted phenyl; d) in compounds of formula 1d, E and E are as defined above; , R2 is hydrogen, C1-C4 alkyl, phenyl, alkylphenyl or cyclo represents lohexylmethyl, Es is hydrogen, linear C1-C4 alkyl or alkyl phenyl] or any pharmaceutically acceptable salt of a compound of formula 1a-d.

Probenecid has the above formula 1a~! Excitatory amino acid antagonists (hereinafter referred to as have been discovered to synergistically enhance the therapeutic activity of compounds (described as compounds). Therefore, this These compounds may be used at lower doses in patients receiving probenecid concomitantly. It will be more effective in the treatment period.

Although the mechanism by which probenecid synergistically enhances its effects is not fully understood, Propeneside slows the rate at which compounds are cleared from the central nervous system and also It is thought that this decreases the excretion rate. Probenecid affects the CNS and the whole body. Both in the circulation increase the prekinetic concentration of these compounds.

As used in this application, a) The term "lower alkyl and C1-C4 alkyl" refers to Branched or straight chain alkyl groups containing atoms, such as methyl, ethyl, n-propylene b) lower alkoxy group, isopropyl, n-butyl, isobutyl, etc. The term "C1-C4 alkoxy group" refers to any group containing l to thgJ carbon atoms. straight-chain or branched alkoxy groups, such as methoxy, ethoxy, n-propoxy, Refers to isopropoquine, n-butoxy, isobutoxy, etc. C) The term "cycloalkyl" refers to cyclohexyl or cyclopentyl Point the base, d> The term "substituted phenyl ring" means a phenyl ring substituted with up to 3 substituents (CII86), each substituent is independently halogen, C8-C4 alkyl, Selected from the group consisting of 01-c4 alkoxy, CF3, OCF, OH1 and UCN be done. These substituents may be the same or different and may be or'hameta or Can be located anywhere in the rose position.

e) The term "alkylphenyl-substituted" refers to the following structures, where m is an integer from 1 to 3: -(CH2)II-CeHr.

The phenyl ring may be substituted as described immediately above.

h) The term ``addition salts that are pharmaceutically acceptable'' refers to addition salts or base Add additional salt.

1) The term "halogen" refers to fluorine, bromine, or chlorine.

J〉The term "trialkylamino" refers to, where n is an integer from 2 to 4. Yes, Alk and Alk each independently represent C1-C4 alkyl, k) "rcyclohexylmethyl" refers to -CHa-CeHte.

The expression "pharmaceutically acceptable base addition salts" is represented by formulas 1a-d. Any non-toxic organic or inorganic base of any of the compounds or intermediates thereof. Intended to apply to salted products. Examples of suitable salt-forming bases include alkaline Potassium metal or alkaline earth metal hydroxides, such as sodium hydroxide, potassium hydroxide ammonia, calcium hydroxide, magnesium hydroxide, or barium hydroxide; ammonia a, and aliphatic, cycloaliphatic, or aromatic organic amines, such as methylamine, dimethylamine, Poly- or dibasic salts including thylamine, trimethylamine, and picoline can be formed with these compounds.

rl! The expression "acid addition salts" is represented by formulas 1a-d. Any toxic organic or inorganic acid addition of any of the basic compounds or their intermediates. Intended to apply to salts. Exemplary inorganic acids that form suitable salts include hydrochloric acid, Hydrobromic acid, sulfuric acid, and phosphoric acid, as well as sodium orthophosphoric acid and hydrogen sulfate. including acid metal salts such as lithium. Exemplary organic acids that form suitable salts includes mohedi and tricarboxylic acids. Examples of such acids are e.g. Acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, Koba 7M, geltaric acid, Fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydride Roximaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, saline Lycylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid, and methanesulfonic acid These are sulfonic acids such as fonic acid and 2-hydroxyethanesulfonic acid. This way The salts may exist in hydrated or substantially fresh water form.

The indole rings depicted in formulas 1a and Ib are always substituted with 2 and 3 positions, and It is also possible that one position may be additionally replaced. These further relate to R. May be substituted as indicated by the possible definitions. R is up to 3 further substitutions 4.5.6 or 7, and these additional substituents are Can be located.

These substituents may be the same or different. In compounds of formula 1a and Ib, R1 and R 2 can represent the same substituent and different substituents.

Formula 1c describes one of the classes of compounds of formula 0 IC that can exist as optical isomers. individual optical isomers or molecules (unless expressly excluded) This term can be thought of as referring to a semi-mixture. Q on chiral stationary phase Field 1 via separation via chromatography or selective crystallization after chiral salt formation. By which techniques known in the art can specific optical isomers be separated and recovered? . Instead, if a specific optical isomer is used as a starting material, the final product to give the corresponding isomer.

As indicated by the E2 substituent in the compound of formula +d, the piperidine ring can further be ．． May be substituted with 5 or 6 positions.

R2 may optionally represent up to two non-hydrogen substituents. just one The non-hydrogen substituent is located at any one position on the veridine ring. too If two non-hydrogen substituents are present, they may be the same or different. R2 is When a non-hydrogen substituent, this substituent is syn or a for phosphono substituents. It is possible that n t i.

All of the compounds of formula [d contain at least two asymmetric centers and are therefore diastereomeric. Regarding these compounds and their intermediates, which may exist as isomers, When referring to racemic mixtures, specific optical isomers, or enantiomers, This is a heki that is interpreted as including a pair. Specific optical isomers are defined herein as or chromatography on a chiral stationary phase, or Methods known in the art, such as resolution by chiral salt formation and subsequent separation with single-alternative crystallization. It can be recovered using the developed technology. HPLC ion exchange chromatography is diastereo It can be used to separate only mer.

Examination of formula 1d shows that the compound is an alkyl bonded to the 3 position of the piperidine ring. It is shown to contain carbonyl functionality in the chain. These compounds are carbo The nyl functional group exists in a state of tautomeric equilibrium that adds ν to the keto-enol equilibrium reaction. Will.

Ia compounds in which X represents S are known in the art.

Synthesis of these compounds, their use as excitatory amino acid antagonists; A method for preparing a pharmaceutical composition from et al. is described in US Pat. It is described in patent 5°051.442. U.S. Patent 5,051,442 A preferred compound is one in which R represents a 4,6-dihalo substituent, X is S, and m is 1. , and Z is H. The most preferred compound is 3-[(carboxyme thio]-2-carboxy4,6-dichloroindole.

Formula 1a where X is C1-C4 alkylene and neither R1 nor R2 contains a heterocycle Compounds of are also known in the art. Use of compounds as excitatory amino acid antagonists and methods of making pharmaceutical compositions therefrom are incorporated herein by reference. U.S. Pat. No. 4,960,786. US Patent 4. ! J60 ．． Preferred compounds of 78G are those in which R represents a 416-dihalo substituent and Z is H is a compound in which X is ethylene. The most preferred compound is 3-[(carboxylic ethyl)-2-carboxy-4,6-dichloroindole.

X is 01-C4 alkylene, and one of R1 or R2 contains a heterocycle Compounds of Formula 1a are currently patent-granted, herein incorporated by reference. Filed on August 1, 1991 with an effective filing date of July 16, 1990 is the subject of US patent application Ser. No. 742.146. This application describes these compounds methods of synthesizing them, their use as excitatory amino acid antagonists, preparations from them A method of making the composition is disclosed. A preferred compound is one in which R is 4°6-dihalo. A compound that is a substituent.

The compound of formula 1b was prepared by Futeru on November 2, 1990, incorporated herein by reference. is the subject of US patent application Ser. No. 077,608,457. This application is a combination of those composition, their use as excitatory amino acid antagonists, and preparations containing them. The method is disclosed. Preferred compounds are those in which R is a 4,6-dihalo substituent and B is is alkyl, Z is hydrogen, and A is phenyl. most preferred The new compound is 3-[(phenacyl)methylaminoco-2-carboxy-4,6- It is dichloroindole.

1L compounds of formula 1c are known in the art and are incorporated herein by reference. European Patent Application No. 0418863 and US counterpart currently granted 1iA *553,431 for U.S. patent filed on July 20, 1990 It is described in. These applications describe their synthesis, excitatory amino acid antagonists and describes their uses and formulations of pharmaceuticals containing them. Favorability The compound is one in which A is methylene and E and E are hydrogen. most preferred The compound with the formula R-4-oxo-5-phosphononorvaline + d is May 17, 1990, known in the field and incorporated herein by @ Teru. No. 525,290. This application describes their synthesis , their use as excitatory amino acid antagonists, and pharmaceutical formulations containing them. is listed. Preferred compounds are those whose stereochemistry is 2R,3S, and E , is hydrogen or 4-alkyl. Preferred compounds include 3-(phosphono acetyl)piperidine-2-carboxylic acid, and 3-(phosphonoacetyl)bihelidine Contains gin-4-methyl-2-carboxylic acid.

Prol\necito is also known in this technical field. This is Merck Sharp Eng. It is commercially available under the trademark name Benemid JR1 from De Dome, and is also the supplier of the song. are also available. Prohenesoto is a uric acid ingredient and is used to treat gout. . Pro\necito is a blocker of renal tubular transport and increases plasma levels of penicillin. Thayil, the pharmacology of proheneside is used to treat DeskReference (Physician's Guidebook) Ji*45 edition, page 1379 Described in detail.

As noted above, compounds of formulas la-Id are excitatory amino acid antagonists. These are entertainment Formula 1 antagonizes the effect that stimulant amino acids have on the NMDA receptor complex ζ Compound a-1b is a strychnine-insensitive compound located on the NMDA receptor complex. Compounds of formulas 1c-Id that bind preferentially to glycine binding sites are NMDA receptors. Formulas 1a-1d preferentially bind to glutamate binding sites located on the body complex. The compounds (hereinafter referred to as compounds) are useful in the treatment of several diseases.

Ischemia, hypoglycemia, and trauma induce extracellular release of glutamate and aspartate into nerve cells. It has been shown to increase potentially toxic levels. these antagonists are characterized by these and elevated glutamate or aspartate concentrations. It is neuroprotective in other conditions in which patients are exposed. Therefore, the compounds are present in the CNS. The nerve tissue involved has been subjected to ischemic, hypoxic, traumatic, or hypoglycemic conditions. Useful to minimize damage when

Typical examples of such ischemic, hypoxic, or hypoglycemic conditions are stroke and ventricular Accidents - carbon oxide poisoning, hyperinsulinemia, cardiac arrest, water accidents, suffocation, brain damage This includes decreased nerve damage following trauma to the spinal cord, and neonatal hypoxic trauma.

In order to effectively minimize the CSNS loss compounds experienced by patients, low M element, Compounds should be administered to patients within 24 hours of the onset of ischemic or hypoglycemic symptoms. Ru.

The compounds exhibit anticonvulsant properties and are useful in the treatment of epilepsy. These are large It is useful in the treatment of seizures, petit mal seizures, psychomotor seizures, autonomous seizures, etc. Compounds Huntington's disease, Alzheimer's disease, senile dementia, type I gelthal acidemia , a lot! Neuronal loss associated with dementia and uncontrolled seizures 1! neuropathy like Useful in treating venereal diseases. These compounds are given to patients who experience these symptoms. This prevents further neurodegeneration in patients and reduces the rate at which neurodegeneration occurs. let As will be clear to those skilled in the art, the compounds may be used as a result of disease or lack of oxygen or sugar. CN S tM (used in this application, which does not correct I) The term "treat" used in this article refers to preventing future injury or reducing the rate at which subsequent injury occurs. The ability of a compound to lower The compounds are also used as anxiolytics and analgesics. It can be used as The therapeutic activity of these compounds is described in the above, incorporated by reference. More fully described in US patents and patent applications.

Compounds may be co-administered with probenecid to treat any of the conditions listed above. I can give. The amount of probenecid required to synergize the therapeutic effects of the compounds is the particular compound of formula 1a-d to be administered, the patient, any other underlying disease within the patient; Depending on the presence of symptoms, etc., there is a wide range of

Typically, proheneside can be administered at a dosage of 0.5-3 g/day. - Repeatedly Repeated administration may be desirable, varying according to the conditions outlined above. probene Cid will typically be administered 2-4 times per day.

Formula 1a~! The appropriate dosage range in which the compound d exhibits this effect depends on the specific disease or patient being treated. the extent of the patient's medical condition, the patient, the particular drug administered, the route of administration, and the patient's internal health. Compounds of formulas 1a-1d that vary widely depending on the collection of other underlying pathologies, etc. The dosage ranges within which the substances exhibit their antagonistic effects are given in Table 1 below.

Table 1 When co-administering proheneside, this dosage range can be adjusted 2 to 10 times lower. . Instead, in order to obtain higher healing BP and enhanced effects due to J degree, Therefore, the compounds can be administered within the same dosage range. The frequency of compound administration depends on the disease being treated. can vary widely depending on the symptoms. Repeated daily administration is preferably as outlined above. It changes according to the conditions. Maintain continuous intravenous infusion in certain conditions such as stroke It may be desirable to do so.

Probenecid is currently available as a tablet. The sodium salt of probenecid is It is readily soluble in water and injectable forms are prepared from this salt using techniques well known to those skilled in the art. can.

The compounds of the present invention vlj can be administered by various &ll.

These are effective when administered orally. Compounds may also be administered parenterally (i.e. It can be administered (subcutaneously, intravenously, intramuscularly, intravenously, or intracapsularly). above us Patents and patent applications teach methods of making pharmaceutical dosage forms containing compounds.

Compounds of formula +a-d and probenecid can be administered in two different pharmaceutical dosage forms. Wear. Instead, compounds and proheneside can be used alone to increase patient convenience. The compound comes in a pharmaceutical dosage format. These pharmaceutical compositions are known in the art. It can be manufactured using a method that has been developed. Typically, antagonistic doses of the compound and probenecid in admixture with a pharmaceutically acceptable carrier.

For oral administration, the two drugs may be taken as capsules, pills, tablets, lozenges, melts, or powders. They can be formulated into solid or liquid preparations such as agents, suspensions, or emulsions. solid unit dosage Forms include surfactants, lubricants, and ingredients such as lactose, sucrose, and corn starch. It can be made into regular gelatin-type capsules containing fillers, and can also be made into sustained-release formulations. Wear. In another 1 g, the two drugs are made of gum arabic, cornstarch, or gelatin. binders such as tin, disintegrants such as potato starch or alginic acid, and Lactose, combined with a lubricant such as thearic acid or magnesium stearate It can be tabletted with tablet bases such as , sucrose and cornstarch. The liquid formulation , aqueous or non-aqueous pharmaceutically acceptable, by dissolving the active ingredient in the entrained solvent. The solvent may contain suspending agents, sweetening agents, flavoring agents, and preservatives known in the art. It can also contain

For parenteral administration, the two drugs are dissolved in a pharmacologically acceptable pharmaceutical carrier; Can be administered as a solution (alpha) or suspension. Examples of suitable pharmaceutical carriers include water, saline, dextrin. with struose solution, fructose solution, ethanol, or oils of animal, vegetable or synthetic origin. be. ! ! The drug carrier may also contain preservatives, buffers, etc. known in the art. combination When things are administered intracapsularly, they can dissolve the brain into the cerebrospinal fluid using this technique.

As used in this application, a) The term 'nine person' refers to, for example, guinea pigs, mice, rats, cats, Refers to warm-blooded animals such as rabbits, dogs, monkeys, chimpanzees, and humans.

b) The term "treat" refers to reducing or slowing the progression of a patient's disease; refers to the ability of compounds to prevent the occurrence of or the appearance of symptoms.

c) The term ``neurodegeneration'' occurs in a manner characteristic of certain diseases and 1! It refers to the gradual death or extinction of a celiac population leading to.

d) The phrase "co-administration" means that probenecid synergizes the antagonistic effects of the compounds of formula I. This refers to administering probenecid at an appropriate time to ensure that the This is simultaneous administration or administration at appropriate but different times. A suitable dosing meter such as It will be obvious to those skilled in the art to establish the image.

The following examples are given to further illustrate the invention, but are not intended to be used in any way. It is not intended to limit the scope of the invention.

Example 1 One way to evaluate the antiepileptic potential of selected compounds is to use This is due to their ability to suppress sound-induced convulsions within.　DBA/ 2J audiogenic mice exhibit convulsions when exposed to loud sounds, and we need to prevent this reduction. The compound is considered an anticonvulsant.

6-8 male DBA/2JIE! In a group of protopathic mice, 3-[(phenacyl) ) Methylaminoco-2-carboxy-4,6-dichloride (hereinafter referred to as compound) Administer intraperitoneally in 4 to 6 doses ranging from 25 to 400 mg/kg. throw Two hours after treatment, mice were placed independently in a glass jar and exposed to 110 decibels for 30 seconds. Exposed to the bell sound stimulus, each mouse exposed to the sound for seizure activity vILlli. II [measured] while T! the dose given and the movements protected at that dose. The 5ED60 was calculated from the graph based on the percentage of the product.

In some mice, probenecid was administered at 100g+g/kgt [intracavitary addition only]. A zero-order E D So was obtained with the modification.

B) The above protocol was modified slightly to prepare compound 3-[(carboxymethyl ) was repeated with thio2-carboxy-4,6-dichloride. The exam is as follows It was carried out in

3-[(carboxymethyl)thio]- in a group of DBA/2J audiogen-sensitive mice. 2-carboxy 4,6-dichloride (hereinafter referred to as compound) in 25-b give 5 minutes after administration, these were placed separately in glass jars and incubated for 30 seconds. Exposure to a 10 dB sound stimulus, each mouse was exposed to the sound for signs of seizure activity. observed while The dose administered and the animal's performance stimulated by that dose. I created a graph based on cents. EDSO was calculated from the graph. another maw Probenecid at 100-g/kg or 200s + 8gl! Add intraluminally The zero-order ED was obtained by conducting the test with only the following changes.

Example 2 Intracerebroventricular administration of quinolinic acid induces chronic rhinoplasty in mice. The occurrence of this spasticity If a compound can be inhibited, it is considered to have anti-epileptic activity. This example is R- Ability of 4-oxo-5-phosphononorvaline to suppress the occurrence of these 114 This shows that probenecid strengthened (synergized)

In this study, different doses of R-4-oxo-5 ranging from 1 to 1.6-g/kg were tested. - Groups of 10 mice were treated intravenously with phosphononorvaline (hereinafter referred to as compound). Pre-treated by route. After 5 minutes, mice were given 7.7 μg of Kino in a volume of 5 μl of saline. Phosphate was administered by intraventricular route. Animals were then examined for signs of chronic seizures for 15 min. Measure the distance. Based on the appropriate dose administered and the percentage of animals that survived at that dose. I then created a graph. ED5o was calculated from the graph. Probenecito intraperitoneally The test was repeated in different mice with the only change being that 100 mg/kg was added to the target route. . The following ED60 was obtained.

The compound was administered intraperitoneally (dose ranged from 0.5 to 3'2+g/kg) and The 0th-order protocol was repeated with the exception that the pretreatment time was extended to 30 minutes. ED5o was obtained.

Copy and translation of amendment) Article 184-8 of the Patent Law submitted on June 17, 1994

Claims (6)

[Claims] 1. An effective amount of broheneside and the formula ▲There are mathematical formulas, chemical formulas, tables, etc.▼Ia▲There are mathematical formulas, chemical formulas, tables, etc.▼Ib ▲There are mathematical formulas, chemical formulas, tables, etc.▼Ic▲There are mathematical formulas, chemical formulas, tables, etc.▼Id [During the ceremony, a) In the compounds of formula Ia, X represents C1-C4 alkylene or S and m is 1 is an integer of ~4, Z is H, C1-C4 alkyl, phenyl, substituted phenyl, or is an alkylphenyl substituent in which the phenyl ring may be optionally substituted. represents hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, Represents CF3, OCF3, OH, NO2 or CN, R1 and R2 are each independent -OH, -OR3, -NR4R5, -OCH2OR3, or -O-(CH2) n-NR6R7, where n is an integer from 1 to 4, and R3 is a C1 to C4 atom. phenyl, substituted phenyl, or the phenyl ring is optionally substituted. represents a possible alkylphenyl substituent, and R4 and R5 each independently represent water. represents hydrogen or C1-C4 alkyl, and R6 and R7 each independently represent hydrogen or C1-C4 alkyl. ~ C4 alkyl, or R6 and R7 together with the adjacent nitrogen atoms represent piperi form a dino, morpholino or pyrrolidino group, provided that X is a C1-C4 alkylene group. , then m must be 0. b) In the compounds of formula Ib, R, Z and R2 are as above a) and B is hydrogen , C1-C4 alkyl, optionally substituted alkylphenyl or -CH2-COR2, Y is SO2 or CO, and A is phenyl , substituted phenyl or C(O)D, where D is defined as R2 above. c) in compounds of formula Ic, E represents hydrogen, C1-C4 alkyl or -CF3; , A represents a methylene or trimethylene bridging group, E1 is hydrogen, C1 to C4 atom alkyl, cycloalkyl, trialkylamino, alkylphenyl, phenyl, or substituted phenyl. d) In the compound of formula Id, E and E1 are as in c) above, E2 is hydrogen, C1 ~C4 alkyl, phenyl, alkylphenyl or cyclohexylmethyl and E5 represents hydrogen, linear C1-C4 alkyl or alkylphenyl. 〕of NMDA acceptance of the compound or any pharmaceutically acceptable salt of the compound of Formulas Ia-d. Manufacture-acceptable amounts that antagonize the effects of excitatory amino acids on the body complex. The effect of excitatory amino acids on the NMDA receptor complex is Pharmaceutical compositions suitable for antagonism. 2. Use of a compound according to claim 1 as a medicament for the treatment of epilepsy. 3. Use of a compound according to claim 1 as a medicament for the treatment of neurodegenerative diseases. 4. claims as a drug to prevent ischemic/hypoxic damage to brain tissue. Use of the compound according to claim 1. 5. Use of a compound according to claim 1 as a medicament for the treatment of anxiety. 6. Use of a compound according to claim 1 as an analgesic.